Our goal is to develop a platform to contribute to deeper understanding of the interplay between radiation physics, chemistry and biology at sub-cellular levels and to facilitate interdisciplinary work on radiobiological research questions. Monte Carlo (MC) methods have been successfully employed to simulate physical properties of radiation, from the macroscopic dose deposition in radiation therapy patients down to the cellular scale to understand relative biological effectiveness. However, no tool currently provides accurate modeling of macroscopic as well as microscopic biological effects of radiation where researchers can define which interactions or structures (organ, cells and sub-cellular structures such as DNA, RNA or cell-membrane) are of interest. Furthermore, MC codes are nearly exclusively used by research physicists because their use requires a learning period that is generally too long for clinical physicists and biological researchers. We thus propose to build on a previously developed MC platform (TOPAS, a TOol for PArticle Simulation) and advance the physical and biological understanding across multiple levels through the detailed modeling of physical and chemical processes. We will offer a new approach to biological modeling by expanding TOPAS to the nanometer scale and include inter- and intra-cellular signaling and radiation response of sub-cellular components. This proposal will lay the foundation for a deeper understanding of the biological effects of radiation in tissues in order to facilitate new research at the boundary between physics and biology. To accomplish this we will: SA1: Customize MC for simulations of fluorescent nuclear track detectors (FNTD) and experimentally validate simulated particle track structures using these FNTDs. SA2: Facilitate chemical tracking of radicals and sub-cellular target (such as DNA, RNA, membrane, mitochondria) response simulation within MC. SA3: Develop a graphical user interface (GUI) and provide an extensible library of sub-cellular geometry components that can be easily exchanged among researchers. SA4: Develop specific model scenarios to carry out foundational research in four selected research topics. The resulting tool, TOPAS-nBio, will facilitate the exchange of ideas and results between physicists and biologists. The flexibility of the proposed TOPAS-nBio, together with open exchange of cell components among researchers, will facilitate communication across fields provide the basis for interdisciplinary collaborations and provide a tool to advance understanding of biological responses to radiation.